RARE DISEASE
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Drug discovery
3,271
papers
On emerging therapies
Overview
Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) are aggressive clonal disorders arising after cytotoxic chemotherapy and/or radiotherapy. Characterized by high-risk genetic abnormalities and poor prognoses, they typically manifest 3–5 years post-treatment, with shorter latency after hematopoietic cell transplantation (HCT) [1][8]. Two distinct subtypes exist: alkylating agent/radiation-associated cases often show TP53 mutations and chromosome 5/7 abnormalities, while topoisomerase II inhibitor-linked cases frequently involve KMT2A rearrangements [1][8][9]. Median survival remains <1 year without allogeneic HCT [1][4].
Population
Primarily affects cancer survivors treated with chemoradiotherapy (e.g., Hodgkin/non-Hodgkin lymphoma, breast cancer) [1][2][9]
Risk elevated by alkylators, radiation, and HCT conditioning regimens [2][8]
10-20% of adult AML/MDS cases; incidence rising with expanded use of DNA-damaging therapies [5][8]
Therapies
Allogeneic HCT remains cornerstone for eligible patients, offering 30-43% long-term survival [1][4][8]
Hypomethylating agents (azacitidine/decitabine) as bridge to transplant or palliative option [6][9]
Supportive care with transfusions, growth factors, and infection prophylaxis for non-HCT candidates [3][9]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
3,271 drug discovery papers about Therapy related acute myeloid leukemia and myelodysplastic syndrome, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
3,271 drug discovery papers about Therapy related acute myeloid leukemia and myelodysplastic syndrome, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-27 | Liposomal-Mitoxantrone Overcomes Acquired Resistance and Enhances Venetoclax Synergy in AML-Mechanistic Insights and Preliminary Clinical Evidence.
Liposomal drug delivery has emerged as a promising strategy to improve the efficacy and safety of chemotherapeutic agents, yet whether and how liposomal reformulation fundamentally reshapes therapeutic response and resistance evolution remains unclear. This study compared liposomal mitoxantrone with free mitoxantrone and examined their effects on antileukemic activity, hematologic toxicity, resistance development, and cell-death pathways. Liposomal and free mitoxantrone were evaluated in an MLL-AF9-driven acute myeloid leukemia mouse model by survival analysis and peripheral blood measurements. Secondary transplantation experiments were performed to evaluate the sensitivity of residual leukemia cells. Single-cell RNA sequencing was used to characterize transcriptional features of residual leukemia cells. Drug combination with venetoclax and the cell killing pattern of the two drugs were explored based on MOLM13 cell line. Exploratory clinical observations were additionally obtained from four patients who received liposomal mitoxantrone in combination with venetoclax. Liposomal mitoxantrone significantly prolonged mouse survival compared with free-mitoxantrone and control groups (both p < 0.001), while causing minimal myelosuppression. In contrast, free-mitoxantrone induced marked hematologic toxicity. Secondary transplantation demonstrated that residual cells following free-mitoxantrone treatment developed resistance upon re-exposure (p < 0.001), while those from liposomal-treated mice retained drug sensitivity and conferred sustained survival benefit (both p < 0.01). Single-cell RNA sequencing revealed that free-mitoxantrone induced transcriptional heterogeneity, characterized by enhanced metabolic and immune-related pathways, and monocyte-like features, whereas liposomal-mitoxantrone preserved a proliferative state similar to untreated cells. Consistently, liposomal-mitoxantrone demonstrated stronger synergistic effects with venetoclax. Liposomal reformulation altered the therapeutic, transcriptional, and cell-death pattern of mitoxantrone in the models. These findings suggest that liposomal mitoxantrone may reduce hematologic toxicity and limit the emergence of drug resistance.
2026-09-25 | Cladribine and low-dose cytarabine as first salvage after hypomethylating agent and venetoclax in acute myeloid leukemia.
The combination of a hypomethylating agent (HMA) and venetoclax (Ven) is the standard frontline therapy for older adults with acute myeloid leukemia (AML) ineligible for intensive chemotherapy and is increasingly used in broader patient populations. However, the optimal approach for patients following progression on HMA/Ven remains undefined. Here, we retrospectively analyze 28 patients with AML who received cladribine plus low-dose cytarabine (Clad/LDAC)-based therapy as second-line treatment after frontline HMA/Ven failure. In this real-world cohort of older patients enriched for secondary AML features, Clad/LDAC-based therapy achieved an overall response rate (ORR) of 41% and composite complete remission (CR/CRi) rate of 33%. Median PFS (mPFS) in responders was 90 days compared to 30 days in non-responders (log-rank p < 0.001), and median OS (mOS) was 185 days versus 66 days (log-rank p = 0.056); for the overall cohort, mPFS was 45 days and mOS was 105 days. Prior HMA/Ven response did not predict Clad/LDAC outcomes, supporting this approach even in patients with primary refractory disease. Genetic risk stratification by ELN 2024 less-intensive-therapy classification was prognostic for both PFS (p = 0.028) and OS (p = 0.012), whereas ELN 2022 was not prognostic. TP53-mutated AML was uniformly refractory to both HMA/Ven and Clad/LDAC, with rapid disease progression and high early mortality following Clad/LDAC treatment. Serial molecular profiling identified heterogeneous patterns of clonal evolution across the treatment trajectory, including exploratory observations of high Clad/LDAC ORR in patients with emergent RAS-pathway clones at HMA/Ven failure. These findings highlight Clad/LDAC-based therapy as a salvage option with modest clinical activity following HMA/Ven.
2026-09-20 | Strategies to prevent post-transplant relapse in acute myeloid leukemia and myelodysplastic syndromes.
Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Post-transplant treatment may provide a third anti-leukemic effect after conditioning-related cytotoxicity has waned and before graft-versus-leukemia immunity is fully established. Prophylactic maintenance is initiated in high-risk patients despite undetectable measurable residual disease (MRD), whereas pre-emptive treatment is triggered by the detection of MRD or declining donor chimerism. Hypomethylating agents (HMAs) are biologically attractive and feasible with post-transplant-adapted dosing, but prophylactic azacitidine did not improve relapse-free or overall survival in a randomized trial. Newer decitabine-based, oral HMA, and venetoclax-containing strategies require confirmation. FMS-like tyrosine kinase 3 (FLT3) inhibitors have the strongest prospective evidence in a molecularly selected population. The QuANTUM-First trial supports quizartinib throughout induction, consolidation, and continuation, including after transplantation, whereas the MORPHO trial directly evaluated post-transplant gilteritinib and identified its clearest benefit in patients with detectable peri-transplant FLT3-internal tandem duplication (FLT3-ITD) MRD. This review traces the evolution of relapse prevention strategies and proposes a practical framework integrating baseline risk, serial MRD assessment, targetable biology, immune intervention, and post-transplant feasibility.
2026-09-17 | Acute Myeloid Leukemia With KMT2A Amplification: A TP53-Alteration-Enriched Subgroup Associated With Chromoanagenesis and Poor Prognosis.
KMT2A amplification (KMT2A-amp) is a rare but aggressive genomic abnormality in acute myeloid leukemia (AML), with limited characterization in prior studies. We retrospectively analyzed 96 patients with AML harboring KMT2A-amp, including 56 newly diagnosed (ND) and 40 relapsed/refractory (RR) cases, with a median age of 68 years. Approximately half of the cases had therapy-related or secondary AML. All cases demonstrated highly complex karyotypes, with frequent -5/del(5q), -7/del(7q), and -17/del(17p). TP53 alteration was present in 93% of patients, whereas other recurrent AML-associated mutations were uncommon, and no AML-defining gene fusions or mutations were identified. In cases evaluated by optical genome mapping, all showed chromoanagenesis involving chromosome 11q23 region. Clinical outcomes were poor, with a median overall survival of 5.5 months in ND and 2.3 months in RR patients. Intensive chemotherapy did not improve survival compared with lower-intensity therapy, whereas venetoclax-based regimens were associated with improved overall survival (7.1 vs 4.6 months; p = 0.04) and event-free survival (6.7 vs 0.17 months; p < 0.01). We conclude that KMT2A-amp AML represents an extremely high-risk subgroup occurring in the context of TP53-associated genomic instability and chromoanagenesis. Its refractoriness to conventional chemotherapy highlights the urgent need for more effective, targeted therapeutic strategies.
2026-09-15 | Chidamide plus venetoclax as effective and safe maintenance therapy in high-risk acute myeloid leukemia and myelodysplastic syndrome post-transplantation.
Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading cause of treatment failure in high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), yet effective maintenance strategies are currently lacking. The combination of chidamide (CHI) and venetoclax (VEN) represents a novel approach. However, real-world data on its use are limited. In this study, eighteen high-risk transplant recipients received maintenance therapy with CHI (5 mg/day on days 1-7 or 1-14) plus VEN (100 mg on day 1, then 200 mg on days 2-7 or 2-14) every 2 months. Endpoints included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and safety. After a median follow-up of 708 days, the 2-year OS and DFS were 73.9% and 56.6%, respectively. The 2-year CIR was 28.9%, and the 2-year NRM rate was 22.5%. The most common adverse events were hematologic, including neutropenia (13 episodes), thrombocytopenia (7), and anemia (7), all of which were manageable. No treatment-related mortality, tumor lysis syndrome, or severe acute graft-versus-host disease (GVHD) occurred. In conclusion, CHI plus VEN as post-transplant maintenance therapy shows encouraging efficacy and a manageable safety profile in high-risk AML/MDS patients, representing a promising strategy for relapse prevention.
antibodies
2026-06-12 | Myeloid Malignancies Beyond the Cell: Targeting the Tumour Microenvironment with Next-Generation Immunotherapies.
Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.
2026-06-10 | Effector-to-target ratio as a translational bottleneck for CD33 T-cell engagers in acute myeloid leukemia: a quantitative reanalysis of AMG 330.
A common, often unstated paradigm in T-cell engager (TCE) translation assumes that target-antigen density and drug exposure are the main efficacy drivers, with effector context secondary. This paradigm is visible in dose-escalation strategies and in the use of high-E:T screens as principal preclinical assays. We tested whether an alternative, receptor-saturation framework better organizes the published AMG 330 record in acute myeloid leukemia (AML). Receptor-saturation arguments motivate two qualitative expectations: at sufficiently high CD33 densities, EC 50 should show little systematic dependence on additional antigen density, and response should become increasingly constrained by effector availability and functional state. We tested these expectations using two statistical reanalyses of published AMG 330 data-log-linear regression of EC 50 on CD33 density across 11 AML cell lines, and a comparative effect-size analysis of effector-to-target (E:T) ratio versus CD33 expression in 38 primary AML samples-integrated with clinical exposure-response findings and effector-augmenting rescue studies. Both expectations were supported. CD33 density did not significantly predict EC 50 across the 3.9-fold range tested ( p = 0.13 ; bootstrap 95% CI on slope includes zero). In primary samples, E:T ratio dominated sustained lysis by approximately an order of magnitude over CD33 expression (92.4 vs. 8.5 percentage points; CD33 effect p = 0.7 , not significant). Clinical exposure-response analyses identified baseline E:T ratio and T-cell PD-1 expression as response correlates. A similar target-effector dissociation has been reported in several other TCE programs. The AMG 330 record is more coherently organized by an effector-context framework than by the conventional target-density-and-exposure paradigm. These findings indicate that endogenous-effector assays, paired target-effector biomarkers, and rational effector-support strategies are likely to be clinically informative complements to conventional cell-line potency and dose-escalation approaches in future CD33 TCE development.
2026-05-20 | A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.
2026-03-20 | Diagnostic updates and research advances in AML-MR: Integrating molecular genetics and immune mechanisms.
Acute myeloid leukaemia, myelodysplasia-related (AML-MR) is a distinct subtype of acute myeloid leukemia defined in the 2022 WHO classification. It is characterized by specific molecular genetic abnormalities and immunological features. In recent years, with the continuous refinement of AML classification criteria and the incorporation of more precise molecular biomarkers into the diagnostic system, the accuracy of diagnosis and the precision of risk stratification have been significantly improved, laying the foundation for personalized treatment. Studies have shown that the development of AML-MR is closely associated with clonal hematopoietic abnormalities and dysregulation of the bone marrow immune microenvironment. This immunosuppressive state not only promotes leukemic progression but also affects therapeutic responses. In terms of treatment, emerging immunotherapies have shown promising advances in AML-MR, offering new directions for improving the prognosis of high-risk patients. This review systematically summarizes recent progress in the classification criteria, molecular genetic mechanisms, immune microenvironment characteristics, and targeted therapeutic strategies of AML-MR, aiming to provide insights for optimizing clinical management and guiding future research.
2026-02-05 | Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor.
Heterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectin-like molecule-1 (CLL1)-specific chimeric antigen receptor (CAR) and a survivin-specific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.
cell therapies
2026-09-27 | Age over sibling: Younger unrelated donors provide superior outcomes compared to sibling donors in fully matched HCT in older AML/MDS patients.
Elderly adults represent a substantial proportion of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, preferential selection of matched related donors (MRD) for elderly allogeneic hematopoietic cell (HCT) recipients is challenged by the excellent outcomes of HCT from unrelated matched donors (MUD). In this retrospective multicenter study, we analyzed overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM at 2 and 5 years) of patients aged ≥ 60 years undergoing HCT for AML/MDS between 2014 and 2024, stratified by donor type and donor age. Among 293 patients (median follow-up 21 months), 75% received MUD transplants. Median donor age was 31 years (MUD) versus 61 years (MRD). Grade 3-4 acute GVHD was more frequent in MRD recipients (14% vs 6%). Two- and five-year OS were 58.2% and 46.8%. MUD recipients had superior 2-year OS (62% vs 47%, p = 0.02) and a trend toward improved 5-year OS. Relapse occurred in 31% (MUD) and 36% (MRD), with 85% within 24 months. Two-year NRM was 16%, primarily infection-related. In multivariable analysis (n = 221), donor age < 30 years independently predicted improved OS and reduced early NRM. Younger unrelated donors, particularly < 30 years, were associated with improved survival, supporting prioritization over elderly siblings.
2026-09-02 | A phase 1 trial of CD123-directed chimeric antigen receptor T-cell therapy in adults with relapsed/refractory acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm.
Patients with relapsed acute myeloid leukemia (AML), particularly following allogeneic stem cell transplant (alloHCT), have extremely limited therapeutic options. CD123 is an AML-associated antigen and represents an attractive target for immunotherapy. We report outcomes of a phase 1 trial evaluating CD123-targeting chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory (r/r) AML or blastic plasmacytoid dendritic cell neoplasm (BPDCN). This was a single center, open-label, phase 1 dose escalation study enrolling patients with either CD123-positive r/r AML (Arm 1) or BPDCN (Arm 2). Patients received autologous or donor-derived allogeneic CD123 CAR T cells following lymphodepletion. The co-primary objectives were to examine safety and anti-tumor activity using an activity-constrained for toxicity design and to determine the recommended phase 2 dose. Secondary objectives included assessments of progression-free and overall survival. We enrolled 41 patients, of whom 21 patients (n = 19 on Arm 1 and n = 2 on Arm 2) received CD123 CAR T-cell infusion. The median age of treated AML patients was 45 years (range: 20-71); the two BPDCN patients were aged 24 and 75 years. Among AML patients, 17 (89%) had undergone prior alloHCT. AML patients received 50 × 106 (n = 2), 200 × 106 (n = 6), or 500 × 106 (n = 11) CAR T cells; BPDCN patients received 100 × 106 CAR T cells. There was no dose-limiting toxicity, prolonged myelosuppression, or graft-versus-host disease. Fourteen (74%) AML patients developed grade ≤ 3 cytokine release syndrome (CRS) and 11 (58%) experienced grade ≤ 2 neurotoxicity. Fifteen of 19 treated AML patients were evaluable for disease response for overall best response, of whom 4 (26.7%) had best response of complete remission, including 2 with incomplete count recovery. Neither patient with BPDCN developed CRS but both experienced grade 1 neurotoxicity. One of 2 BPDCN patients achieved CR and relapsed at 3 months. CAR T cell expansion was dose-dependent, but persistence was limited. CD123-directed CAR T-cell therapy is feasible and demonstrates a favorable safety profile in patients with r/r AML and BPDCN, including those with prior alloHCT. Although the estimated overall complete remission rate was modest, these findings provide a foundation for further optimization of CD123 CAR T-cell design, patient selection, and combination strategies. This trial was registered at ClinicalTrials.gov as NCT02159495.
2026-07-15 | Simultaneous Leukocytapheresis and Continuous Renal Replacement Therapy for Acute Myeloid Leukemia: A Case Report.
Hyperleukocytosis in acute myeloid leukemia (AML) could cause life-threatening complications, including leukostasis and tumor lysis syndrome (TLS). While leukocytapheresis and continuous renal replacement therapy (CRRT) are typically performed independently to maintain hemodynamic stability and manage anticoagulation, their simultaneous application is rarely reported. We report a case of a deteriorating patient with secondary AML treated with simultaneous leukocytapheresis and CRRT. For the CRRT circuit, two separate hemodialysis catheters were placed in the femoral vein (access) and internal jugular vein (return). The leukocytapheresis circuit was then connected to the CRRT return line. The procedure was completed without immediate bleeding or thrombotic complications. Reductions in white blood cell counts, ammonia, and lactic acid levels were observed, along with improved oxygenation. Simultaneous leukocytapheresis and CRRT can be a safe and effective modality for the urgent management of hyperleukocytosis and TLS in critically ill patients.
2026-06-30 | T-cell replete haploidentical transplantation compared to mismatched unrelated allogeneic transplantation with post-transplantation cyclophosphamide in patients with secondary acute myeloid leukemia in first complete remission: A study from the ALWP/EBMT.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for secondary acute myeloid leukemia (sAML). Post-transplant cyclophosphamide has improved graft-versus-host disease (GVHD) prophylaxis, enabling the broader use of alternative donors. For patients lacking a human leukocyte antigen (HLA)-matched donor, haploidentical donor (Haplo) or 9/10 HLA mismatched unrelated donor (MMUD) HSCTs are widely used, yet their relative effectiveness in sAML is uncertain. We retrospectively compared outcomes after Haplo versus MMUD HSCT in adults with sAML in first complete remission transplanted between 2010 and 2022. Among 711 patients, 602 received Haplo and 109 MMUD grafts. Patient and transplant characteristics differed between cohorts, including donor age, conditioning intensity, graft source, and transplant year. Neutrophil recovery was faster after MMUD transplantation, while platelet recovery was comparable. Rates of acute and chronic GVHD, relapse incidence, non-relapse mortality, overall survival, leukemia-free survival, and GVHD-free/relapse-free survival were similar. Reduced intensity conditioning lowered acute GVHD risk, while peripheral blood grafts increased chronic GVHD. Lower Karnofsky score, older age and adverse-risk cytogenetics were adverse prognostic factors. Haplo and MMUD transplantation demonstrated comparable efficacy and safety with post-transplant cyclophosphamide, supporting both approaches as viable alternatives in the absence of an HLA-matched donor.
2026-06-25 | UCMSC-Exo for chemotherapy-induced myelosuppression in acute myeloid leukemia: a phase I clinical trial protocol.
Myelosuppression induced by chemotherapy represents a critical bottleneck for patients with hematological malignancies, leading to a series of severe complications responsible for chemotherapy dose reduction, interruptions, and even treatment-related death. There exists an urgent need for strategies to repair the bone marrow microenvironment and thus promote early recovery from myelosuppression. Umbilical cord-derived mesenchymal stem cell exosomes (UCMSC-Exo), as the key effector of stem cells, exhibit multi-target characteristics, making them a promising candidate for bone marrow structural reconstruction and functional remodeling. This study is a single-arm, open-label, dose-escalation, single-center, phase I clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of UCMSC-Exo in the treatment of chemotherapy-induced myelosuppression in patients with acute myeloid leukemia. Nine to eighteen eligible participants will be enrolled sequentially into three UCMSC-Exo dose-escalation groups to receive a single infusion, after which they will be followed up for 12 months. The primary endpoints focus on safety and tolerability. Secondary endpoints include parameters assessing myelosuppression recovery, the incidence of myelosuppression-related complications, and supportive care. The study protocol has been approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.Clinical trial registration: NCT06245746.
proteins
2026-08-12 | Treatment Modalities and the Impact of Granulocyte Colony-Stimulating Factor in AML Patients Treated With Venetoclax and Azacitidine: A DATAML Registry Study.
Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
2025-09-21 | Pathogenic mechanisms and targeted therapies for anemia in myelodysplastic syndromes.
Myelodysplastic Syndromes (MDS) are malignant neoplasms of the myeloid lineage originating from hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis, blood cell dysplasia, and a high risk of transformation to acute leukemia. Anemia affects up to 90 % of MDS patients, significantly increasing symptom burden, impacting quality of life, accelerating disease progression, and is associated with increased morbidity and mortality. The limited therapeutic landscape for addressing anemia in MDS presents a significant challenge in clinical management. This review explores the mechanisms of anemia in MDS（including low-risk MDS and high-risk MDS）, covering disturbances in hematopoiesis, telomere dynamics, inflammation, immune dysregulation, alterations in iron metabolism, and the role of the bone marrow microenvironment. We examine how these factors contribute to the complex pathophysiology of MDS-related anemia and discuss their implications for treatment strategies. Furthermore, we highlight recent advances in understanding the molecular basis of MDS, which have paved the way for novel therapeutic approaches. These include targeted therapies addressing specific genetic mutations, immunomodulatory agents, and innovative approaches to stimulate effective erythropoiesis. We also review emerging treatments such as Luspatercept, along with other novel agents targeting specific pathways, and ongoing clinical trials exploring combination therapies and personalized treatment strategies.
2025-05-28 | Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial.
6512 Background: In the phase 3 COMMANDS trial (NCT03682536), LUSPA was superior in improving red blood cell (RBC)-TI ≥12 wks with concurrent hemoglobin increase ≥1.5 g/dL in Wks 1 to 24 vs EA and had durable clinical benefit in pts with ESA-naive transfusion-dependent (TD) lower-risk MDS (LR-MDS; Della Porta MG, et al. Lancet Haematol . 2024; Garcia-Manero G, et al. ASH. 2024). Here, we report updated results including OS and duration of response. Methods: Eligible pts (≥18 yrs; ESA-naive; RBC TD; very low/low/intermediate-risk MDS) were randomized 1:1 (stratified by baseline [BL] RBC transfusion burden [TB], serum erythropoietin [EPO] level, and ring sideroblast [RS] status) to receive LUSPA (1.0-1.75 mg/kg) SC Q3W or EA (450-1050 IU/kg; max dose 80,000 IU) SC QW for ≥24 wks. Secondary endpoints included OS, duration of RBC-TI ≥12 wks, and safety. Results: As of Nov 4, 2024, median follow up (FU) was 29.0 and 27.1 mos for the LUSPA (n=182) and EA (n=181) groups, respectively. Median OS for LUSPA was not reached (NR) and was 46.7 mos for EA (HR, 0.86; 95% CI, 0.60-1.24); 3-yr OS rates were 63.8% and 62.2%, respectively, and 5-yr OS rates were 54.0% and 41.8%. In subgroups, similar OS trends were observed (Table). Overall, RBC-TI ≥12 wks (Wk 1 to end of treatment [EOT]) was reached by 76.4% (139/182) of pts in the LUSPA group and 55.8% (101/181) in the EA group. Median cumulative duration (95% CI) of RBC-TI ≥12 wks (sum of all durations of RBC-TI ≥12 wks episodes from Wk 1 to EOT) was 187.3 (119.6-NE) wks for LUSPA vs 94.9 (73.1-179.0) wks for EA (HR, 0.51; 95% CI, 0.34-0.77). Median duration (95% CI) of longest RBC-TI ≥12 wks period (from Wk 1 to EOT) was 126.6 (81.0-184.4) vs 86.7 (55.9-111.1) wks (HR, 0.64; 95% CI, 0.44-0.93). At cutoff, 24.7% of LUSPA pts and 11.2% of EA pts were on treatment; 84.6% and 82.7%, respectively, had ≥1 dose escalation. With longer FU, no new safety concerns emerged. Deaths occurred in both groups on- (10.4% vs 9.5%) and post-treatment (20.9% vs 26.3%). Progression to acute myeloid leukemia was comparable between groups (3.8% vs 4.4%). Conclusions: LUSPA led to improvements in response rate and duration, with a positive OS trend requiring further evaluation through more extended follow up. LUSPA signifies a new standard of care for anemia in first-line LR-MDS. Clinical trial information: NCT03682536 . Median OS, mos LUSPA EA HR (95% CI) Overall (ITT) (n=182)NR (n=181)46.7 0.86 (0.60-1.24) Stratification subgroup BL TB <4 U (n=118)NR (n=111)46.7 0.87(0.55-1.38) BL TB ≥4 U (n=64)NR (n=70)48.2 0.74(0.42-1.31) RS+ (n=133)NR (n=130)48.2 0.77(0.50-1.19) RS− (n=49)NR (n=50)46.2 0.93(0.50-1.75) BL EPO ≤200 U/L (n=145)NR (n=144)51.4 0.84(0.55-1.27) BL EPO >200 U/L (n=37)NR (n=37)35.4 0.81(0.40-1.64) ITT, intention-to-treat; U, units.
2024-07-12 | The Impact of Prophylactic Post-Chemotherapy G-CSF on the Relapse Rates in Patients with Acute Myeloid Leukemia: A Meta-Analysis.
This meta-analysis evaluated the impact of prophylactic post-chemotherapy granulocyte colony-stimulating factor (G-CSF) in patients with acute myeloid leukemia (AML). Overall, the relapse rate, overall survival, event-free survival, and mortality rate were similar in G-CSF (+) compared to G-CSF (-) patients. However, the relative risk (RR) of relapse was higher in children and in secondary AML patients who were treated with G-CSF compared to the G-CSF (-) group [RR, 95% confidence interval: 1.26, 1.04-1.52, and 1.12 (1.02-1.24)]. Treatment with post-chemotherapy G-CSF should be prescribed with caution in pediatric patients with AML and secondary AML as possibly increasing the relapse risk.
2024-02-27 | Treatment with the apoptosis inhibitor Asunercept reduces clone sizes in patients with lower risk Myelodysplastic Neoplasms
Abstract In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2–6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5–39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation ( n = 1 DNMT3A , n = 1 IDH2 , n = 1 TET2 ). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.
other
2026-08-24 | The roles of RUNX1 in megakaryocyte differentiation in myeloid leukemia.
Runt-related transcription factor 1/acute myeloid leukemia 1 (RUNX1/AML1) is essential for the generation of myeloid progenitor cells and differentiation of megakaryocytes (MKs). During megakaryocyte differentiation and maturation, RUNX1 forms transcriptional complexes with transcription factors such as GATA-1, Ets-1, Fli-1, and NF-E2 to promote platelet production. Disruption of RUNX1 is implicated in hematopoietic neoplasms like familial platelet disorder (FPD/AML), myelodysplastic syndrome (MDS) and acute myeloid leukemia. Here, we review the transcriptional regulation of RUNX1 in megakaryocyte differentiation of normal individuals and myeloid leukemia patients. We also summarize post-translational modifications (PTMs) of RUNX1 and discuss their potential implications for novel RUNX1-directed leukemia therapies.
2026-04-01 | mRNA vaccines in cancer immunotherapy: current progress and perspectives in solid tumors and hematologic malignancies.
The unprecedented success of mRNA vaccines during the COVID-19 pandemic has accelerated the development of nucleic acid-based therapeutics, particularly in oncology. Decades of foundational research on mRNA design, delivery, and immunogenicity have laid the groundwork for the application of mRNA vaccines in cancer treatment. Herein, we summarize the key principles of synthetic mRNA engineering, including the optimization of structural elements, nucleoside modification, and codon usage to improve stability, enhance translation efficiency, and modulate immune responses. We highlight diverse antigen strategies, including tumor-associated antigens; neoantigens; and novel sources, such as cryptic antigens, aberrant splicing variants, and transposable element-derived antigens. We discuss delivery platforms, particularly lipid nanoparticles (LNPs) and dendritic cell-based systems, in the context of improving mRNA biodistribution and immune activation. We further examine how mRNA vaccines stimulate antitumor responses by encoding antigens, modulating the tumor microenvironment, and supporting adoptive T cell therapies. We review preclinical and clinical advances in combining mRNA vaccine with immune checkpoint inhibitors for the treatment of solid tumors (e.g., melanoma, pancreatic cancer, and glioblastoma) and hematologic malignancies (e.g., acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma). Finally, we explore emerging innovations, such as targeted LNP platforms for in vivo chimeric antigen receptor T/T cell receptor T engineering and artificial intelligence-assisted vaccine design, underscoring the transformative potential of mRNA technology in cancer immunotherapy.
2025-10-18 | Acute Leukemias of Ambiguous Lineage With RUNX1 Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With RUNX1 Mutations: A Study From the Bone Marrow Pathology Group.
The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS-related AML (AML-MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi-institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS-related cytogenetics, BCR::ABL1, KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL-RUNX1 and AML-RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS-associated genes. No ALAL-RUNX1 or AML-RUNX1 cases showed concomitant TP53 mutation. ALAL-RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML-directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL-RUNX1; however, it did not reach significance. Our results suggest ALAL-RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML-RUNX1. Our findings suggest, like other MR mutations, RUNX1-mutated ALALs should be included within AML-MR.
2025-04-21 | Abstract 6500: Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms
Abstract Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with cytogenetic abnormalities of chromosome 7 have dismal survival outcomes. Monosomy 7 or deletion of 7q (-7/del7q) are adverse-risk cytogenetic features found in up to 12% of MDS/AML patients and are further enriched in therapy-related MDS/AML. Despite significant scientific effort, no targeted therapy is available for patients with -7/del7q MDS/AML. Several genes are associated with -7/del7q leukemogenesis. Cut-like homeobox 1 (CUX1) is a gene encoding a context-dependent transcription factor required for several molecular pathways, including epigenetic signaling. CUX1 is deleted in -7/del7q MDS/AML and somatically mutated in 2-4% of MDS/AML. CUX1 mutations and CUX1 deletions are associated with a poor prognosis, and are known to co-occur with adverse risk TP53 mutations and a complex cytogenetic background. Thus, there is a need for novel human models of MDS/AML to isolate the effect of CUX1 alterations. To address the need for high-fidelity models of MDS/AML with high-risk genetic changes, we transfected human inducible pluripotent stem cells (hiPSCs) with CUX1 targeting gRNA and CRISPR/Cas9 ribonucleotide-protein (RNP) complexes to generate isogenic hiPSC lines bearing CUX1+/- and CUX1-/- genotypes alongside parent hiPSCs and sham transfection lines with a CUX1+/+ background. These derivative cell lines underwent rigorous validation by karyotypic G-banding analysis, sequencing, immunoblotting, trilineage germ layer differentiation, and analysis of hiPSC transcriptional and immunophenotypic markers. We hypothesized that the loss of one or both alleles of CUX1 would result in transcriptional changes similar to CUX1 mutated and -7/del7q MDS/AML. This model can be further leveraged to identify potential treatment targets. We obtained bulk RNA sequencing of undifferentiated hiPSCs and hiPSC-derived hematopoietic stem and progenitor cells (i-HSPCs) of each genotype (CUX1+/+, CUX1+/-, and CUX1-/-). We identified several differentially expressed genes and novel long non-coding RNAs in hiPSCs with Cas9-mediated CUX1 deletions, including downregulation of distinct subsets of genes in CUX1-/- and CUX1+/- hiPSCs. Bulk RNA sequencing of CUX1-/- and CUX1+/- i-HSPCs identified an association between reduced expression of thioredoxin-interacting protein (TXNIP), a known regulator of autophagy. This study supports the use of hiPSC-based CRISPR/Cas9 gene editing as a novel platform to identify gene-specific alterations in genotypically and cytogenetically complex myeloid neoplasms. Citation Format: Joseph Michael Cannova, Kaina A. Millan, Yuqing Xue, Aubrianna S. Ramsland, Zara Khosravi, Adesewa Ogunsusi, Matthew Jotte, Megan McNerney, Michael Drazer. Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6500.
2024-10-29 | AML-VAC-XS15-01: protocol of a first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of a multi-peptide vaccine based on leukemia stem cell antigens in acute myeloid leukemia patients.
Acute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome. Based on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial's primary objectives are the assessment of the vaccine's immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy. The AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.
small molecules
2026-09-27 | Liposomal-Mitoxantrone Overcomes Acquired Resistance and Enhances Venetoclax Synergy in AML-Mechanistic Insights and Preliminary Clinical Evidence.
Liposomal drug delivery has emerged as a promising strategy to improve the efficacy and safety of chemotherapeutic agents, yet whether and how liposomal reformulation fundamentally reshapes therapeutic response and resistance evolution remains unclear. This study compared liposomal mitoxantrone with free mitoxantrone and examined their effects on antileukemic activity, hematologic toxicity, resistance development, and cell-death pathways. Liposomal and free mitoxantrone were evaluated in an MLL-AF9-driven acute myeloid leukemia mouse model by survival analysis and peripheral blood measurements. Secondary transplantation experiments were performed to evaluate the sensitivity of residual leukemia cells. Single-cell RNA sequencing was used to characterize transcriptional features of residual leukemia cells. Drug combination with venetoclax and the cell killing pattern of the two drugs were explored based on MOLM13 cell line. Exploratory clinical observations were additionally obtained from four patients who received liposomal mitoxantrone in combination with venetoclax. Liposomal mitoxantrone significantly prolonged mouse survival compared with free-mitoxantrone and control groups (both p < 0.001), while causing minimal myelosuppression. In contrast, free-mitoxantrone induced marked hematologic toxicity. Secondary transplantation demonstrated that residual cells following free-mitoxantrone treatment developed resistance upon re-exposure (p < 0.001), while those from liposomal-treated mice retained drug sensitivity and conferred sustained survival benefit (both p < 0.01). Single-cell RNA sequencing revealed that free-mitoxantrone induced transcriptional heterogeneity, characterized by enhanced metabolic and immune-related pathways, and monocyte-like features, whereas liposomal-mitoxantrone preserved a proliferative state similar to untreated cells. Consistently, liposomal-mitoxantrone demonstrated stronger synergistic effects with venetoclax. Liposomal reformulation altered the therapeutic, transcriptional, and cell-death pattern of mitoxantrone in the models. These findings suggest that liposomal mitoxantrone may reduce hematologic toxicity and limit the emergence of drug resistance.
2026-09-25 | Cladribine and low-dose cytarabine as first salvage after hypomethylating agent and venetoclax in acute myeloid leukemia.
The combination of a hypomethylating agent (HMA) and venetoclax (Ven) is the standard frontline therapy for older adults with acute myeloid leukemia (AML) ineligible for intensive chemotherapy and is increasingly used in broader patient populations. However, the optimal approach for patients following progression on HMA/Ven remains undefined. Here, we retrospectively analyze 28 patients with AML who received cladribine plus low-dose cytarabine (Clad/LDAC)-based therapy as second-line treatment after frontline HMA/Ven failure. In this real-world cohort of older patients enriched for secondary AML features, Clad/LDAC-based therapy achieved an overall response rate (ORR) of 41% and composite complete remission (CR/CRi) rate of 33%. Median PFS (mPFS) in responders was 90 days compared to 30 days in non-responders (log-rank p < 0.001), and median OS (mOS) was 185 days versus 66 days (log-rank p = 0.056); for the overall cohort, mPFS was 45 days and mOS was 105 days. Prior HMA/Ven response did not predict Clad/LDAC outcomes, supporting this approach even in patients with primary refractory disease. Genetic risk stratification by ELN 2024 less-intensive-therapy classification was prognostic for both PFS (p = 0.028) and OS (p = 0.012), whereas ELN 2022 was not prognostic. TP53-mutated AML was uniformly refractory to both HMA/Ven and Clad/LDAC, with rapid disease progression and high early mortality following Clad/LDAC treatment. Serial molecular profiling identified heterogeneous patterns of clonal evolution across the treatment trajectory, including exploratory observations of high Clad/LDAC ORR in patients with emergent RAS-pathway clones at HMA/Ven failure. These findings highlight Clad/LDAC-based therapy as a salvage option with modest clinical activity following HMA/Ven.
2026-09-20 | Strategies to prevent post-transplant relapse in acute myeloid leukemia and myelodysplastic syndromes.
Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Post-transplant treatment may provide a third anti-leukemic effect after conditioning-related cytotoxicity has waned and before graft-versus-leukemia immunity is fully established. Prophylactic maintenance is initiated in high-risk patients despite undetectable measurable residual disease (MRD), whereas pre-emptive treatment is triggered by the detection of MRD or declining donor chimerism. Hypomethylating agents (HMAs) are biologically attractive and feasible with post-transplant-adapted dosing, but prophylactic azacitidine did not improve relapse-free or overall survival in a randomized trial. Newer decitabine-based, oral HMA, and venetoclax-containing strategies require confirmation. FMS-like tyrosine kinase 3 (FLT3) inhibitors have the strongest prospective evidence in a molecularly selected population. The QuANTUM-First trial supports quizartinib throughout induction, consolidation, and continuation, including after transplantation, whereas the MORPHO trial directly evaluated post-transplant gilteritinib and identified its clearest benefit in patients with detectable peri-transplant FLT3-internal tandem duplication (FLT3-ITD) MRD. This review traces the evolution of relapse prevention strategies and proposes a practical framework integrating baseline risk, serial MRD assessment, targetable biology, immune intervention, and post-transplant feasibility.
2026-09-17 | Acute Myeloid Leukemia With KMT2A Amplification: A TP53-Alteration-Enriched Subgroup Associated With Chromoanagenesis and Poor Prognosis.
KMT2A amplification (KMT2A-amp) is a rare but aggressive genomic abnormality in acute myeloid leukemia (AML), with limited characterization in prior studies. We retrospectively analyzed 96 patients with AML harboring KMT2A-amp, including 56 newly diagnosed (ND) and 40 relapsed/refractory (RR) cases, with a median age of 68 years. Approximately half of the cases had therapy-related or secondary AML. All cases demonstrated highly complex karyotypes, with frequent -5/del(5q), -7/del(7q), and -17/del(17p). TP53 alteration was present in 93% of patients, whereas other recurrent AML-associated mutations were uncommon, and no AML-defining gene fusions or mutations were identified. In cases evaluated by optical genome mapping, all showed chromoanagenesis involving chromosome 11q23 region. Clinical outcomes were poor, with a median overall survival of 5.5 months in ND and 2.3 months in RR patients. Intensive chemotherapy did not improve survival compared with lower-intensity therapy, whereas venetoclax-based regimens were associated with improved overall survival (7.1 vs 4.6 months; p = 0.04) and event-free survival (6.7 vs 0.17 months; p < 0.01). We conclude that KMT2A-amp AML represents an extremely high-risk subgroup occurring in the context of TP53-associated genomic instability and chromoanagenesis. Its refractoriness to conventional chemotherapy highlights the urgent need for more effective, targeted therapeutic strategies.
2026-09-15 | Chidamide plus venetoclax as effective and safe maintenance therapy in high-risk acute myeloid leukemia and myelodysplastic syndrome post-transplantation.
Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading cause of treatment failure in high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), yet effective maintenance strategies are currently lacking. The combination of chidamide (CHI) and venetoclax (VEN) represents a novel approach. However, real-world data on its use are limited. In this study, eighteen high-risk transplant recipients received maintenance therapy with CHI (5 mg/day on days 1-7 or 1-14) plus VEN (100 mg on day 1, then 200 mg on days 2-7 or 2-14) every 2 months. Endpoints included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and safety. After a median follow-up of 708 days, the 2-year OS and DFS were 73.9% and 56.6%, respectively. The 2-year CIR was 28.9%, and the 2-year NRM rate was 22.5%. The most common adverse events were hematologic, including neutropenia (13 episodes), thrombocytopenia (7), and anemia (7), all of which were manageable. No treatment-related mortality, tumor lysis syndrome, or severe acute graft-versus-host disease (GVHD) occurred. In conclusion, CHI plus VEN as post-transplant maintenance therapy shows encouraging efficacy and a manageable safety profile in high-risk AML/MDS patients, representing a promising strategy for relapse prevention.
antibodies
2026-06-12 | Myeloid Malignancies Beyond the Cell: Targeting the Tumour Microenvironment with Next-Generation Immunotherapies.
Myeloid malignancies encompass a heterogeneous group of haematological disorders, primarily including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs). MDS is characterised by defective myeloid cell maturation, while MPNs involve the pathological overproduction of myeloid lineage cells. In the absence of timely diagnosis and effective clinical intervention, both entities carry a substantial risk of progression to acute myeloid leukaemia (AML). Although allogeneic haematopoietic stem cell transplantation remains the only potentially curative therapy, its application is frequently constrained by patient-related factors such as advanced age and comorbid conditions. While currently, hypomethylating agent therapy (azacitidine and decitabine) is mainly used in high-risk MDS patients, and ruxolitinib is primarily used in symptomatic primary myelofibrosis (PMF-MPN), their clinical efficacy remains suboptimal. More recently, focus has turned toward the role of the tumour microenvironment (TME) in disease pathogenesis and whether therapeutically targeting the TME, either alone or in combination with conventional therapy, could present a new treatment option. Emerging evidence underscores the significant influence of TME components, particularly macrophages and T cells, in modulating immune responses and shaping the leukaemic niche to either facilitate or hinder malignant progression. In response, a new generation of immune checkpoint inhibitors are being developed to target the TME, including PD-1/CTLA-4 blockers, macrophage-directed agents including CD47 inhibitors, and T cell-targeting checkpoint inhibitors such as TIM-1 and LAG-3. This review will describe the functional role of key TME constituents in the progression of myeloid malignancies and explore the current landscape and future potential of advanced cellular and molecular immunotherapies in the treatment of these disorders.
2026-06-10 | Effector-to-target ratio as a translational bottleneck for CD33 T-cell engagers in acute myeloid leukemia: a quantitative reanalysis of AMG 330.
A common, often unstated paradigm in T-cell engager (TCE) translation assumes that target-antigen density and drug exposure are the main efficacy drivers, with effector context secondary. This paradigm is visible in dose-escalation strategies and in the use of high-E:T screens as principal preclinical assays. We tested whether an alternative, receptor-saturation framework better organizes the published AMG 330 record in acute myeloid leukemia (AML). Receptor-saturation arguments motivate two qualitative expectations: at sufficiently high CD33 densities, EC 50 should show little systematic dependence on additional antigen density, and response should become increasingly constrained by effector availability and functional state. We tested these expectations using two statistical reanalyses of published AMG 330 data-log-linear regression of EC 50 on CD33 density across 11 AML cell lines, and a comparative effect-size analysis of effector-to-target (E:T) ratio versus CD33 expression in 38 primary AML samples-integrated with clinical exposure-response findings and effector-augmenting rescue studies. Both expectations were supported. CD33 density did not significantly predict EC 50 across the 3.9-fold range tested ( p = 0.13 ; bootstrap 95% CI on slope includes zero). In primary samples, E:T ratio dominated sustained lysis by approximately an order of magnitude over CD33 expression (92.4 vs. 8.5 percentage points; CD33 effect p = 0.7 , not significant). Clinical exposure-response analyses identified baseline E:T ratio and T-cell PD-1 expression as response correlates. A similar target-effector dissociation has been reported in several other TCE programs. The AMG 330 record is more coherently organized by an effector-context framework than by the conventional target-density-and-exposure paradigm. These findings indicate that endogenous-effector assays, paired target-effector biomarkers, and rational effector-support strategies are likely to be clinically informative complements to conventional cell-line potency and dose-escalation approaches in future CD33 TCE development.
2026-05-20 | A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.
2026-03-20 | Diagnostic updates and research advances in AML-MR: Integrating molecular genetics and immune mechanisms.
Acute myeloid leukaemia, myelodysplasia-related (AML-MR) is a distinct subtype of acute myeloid leukemia defined in the 2022 WHO classification. It is characterized by specific molecular genetic abnormalities and immunological features. In recent years, with the continuous refinement of AML classification criteria and the incorporation of more precise molecular biomarkers into the diagnostic system, the accuracy of diagnosis and the precision of risk stratification have been significantly improved, laying the foundation for personalized treatment. Studies have shown that the development of AML-MR is closely associated with clonal hematopoietic abnormalities and dysregulation of the bone marrow immune microenvironment. This immunosuppressive state not only promotes leukemic progression but also affects therapeutic responses. In terms of treatment, emerging immunotherapies have shown promising advances in AML-MR, offering new directions for improving the prognosis of high-risk patients. This review systematically summarizes recent progress in the classification criteria, molecular genetic mechanisms, immune microenvironment characteristics, and targeted therapeutic strategies of AML-MR, aiming to provide insights for optimizing clinical management and guiding future research.
2026-02-05 | Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor.
Heterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectin-like molecule-1 (CLL1)-specific chimeric antigen receptor (CAR) and a survivin-specific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.
cell therapies
2026-09-27 | Age over sibling: Younger unrelated donors provide superior outcomes compared to sibling donors in fully matched HCT in older AML/MDS patients.
Elderly adults represent a substantial proportion of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, preferential selection of matched related donors (MRD) for elderly allogeneic hematopoietic cell (HCT) recipients is challenged by the excellent outcomes of HCT from unrelated matched donors (MUD). In this retrospective multicenter study, we analyzed overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM at 2 and 5 years) of patients aged ≥ 60 years undergoing HCT for AML/MDS between 2014 and 2024, stratified by donor type and donor age. Among 293 patients (median follow-up 21 months), 75% received MUD transplants. Median donor age was 31 years (MUD) versus 61 years (MRD). Grade 3-4 acute GVHD was more frequent in MRD recipients (14% vs 6%). Two- and five-year OS were 58.2% and 46.8%. MUD recipients had superior 2-year OS (62% vs 47%, p = 0.02) and a trend toward improved 5-year OS. Relapse occurred in 31% (MUD) and 36% (MRD), with 85% within 24 months. Two-year NRM was 16%, primarily infection-related. In multivariable analysis (n = 221), donor age < 30 years independently predicted improved OS and reduced early NRM. Younger unrelated donors, particularly < 30 years, were associated with improved survival, supporting prioritization over elderly siblings.
2026-09-02 | A phase 1 trial of CD123-directed chimeric antigen receptor T-cell therapy in adults with relapsed/refractory acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm.
Patients with relapsed acute myeloid leukemia (AML), particularly following allogeneic stem cell transplant (alloHCT), have extremely limited therapeutic options. CD123 is an AML-associated antigen and represents an attractive target for immunotherapy. We report outcomes of a phase 1 trial evaluating CD123-targeting chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory (r/r) AML or blastic plasmacytoid dendritic cell neoplasm (BPDCN). This was a single center, open-label, phase 1 dose escalation study enrolling patients with either CD123-positive r/r AML (Arm 1) or BPDCN (Arm 2). Patients received autologous or donor-derived allogeneic CD123 CAR T cells following lymphodepletion. The co-primary objectives were to examine safety and anti-tumor activity using an activity-constrained for toxicity design and to determine the recommended phase 2 dose. Secondary objectives included assessments of progression-free and overall survival. We enrolled 41 patients, of whom 21 patients (n = 19 on Arm 1 and n = 2 on Arm 2) received CD123 CAR T-cell infusion. The median age of treated AML patients was 45 years (range: 20-71); the two BPDCN patients were aged 24 and 75 years. Among AML patients, 17 (89%) had undergone prior alloHCT. AML patients received 50 × 106 (n = 2), 200 × 106 (n = 6), or 500 × 106 (n = 11) CAR T cells; BPDCN patients received 100 × 106 CAR T cells. There was no dose-limiting toxicity, prolonged myelosuppression, or graft-versus-host disease. Fourteen (74%) AML patients developed grade ≤ 3 cytokine release syndrome (CRS) and 11 (58%) experienced grade ≤ 2 neurotoxicity. Fifteen of 19 treated AML patients were evaluable for disease response for overall best response, of whom 4 (26.7%) had best response of complete remission, including 2 with incomplete count recovery. Neither patient with BPDCN developed CRS but both experienced grade 1 neurotoxicity. One of 2 BPDCN patients achieved CR and relapsed at 3 months. CAR T cell expansion was dose-dependent, but persistence was limited. CD123-directed CAR T-cell therapy is feasible and demonstrates a favorable safety profile in patients with r/r AML and BPDCN, including those with prior alloHCT. Although the estimated overall complete remission rate was modest, these findings provide a foundation for further optimization of CD123 CAR T-cell design, patient selection, and combination strategies. This trial was registered at ClinicalTrials.gov as NCT02159495.
2026-07-15 | Simultaneous Leukocytapheresis and Continuous Renal Replacement Therapy for Acute Myeloid Leukemia: A Case Report.
Hyperleukocytosis in acute myeloid leukemia (AML) could cause life-threatening complications, including leukostasis and tumor lysis syndrome (TLS). While leukocytapheresis and continuous renal replacement therapy (CRRT) are typically performed independently to maintain hemodynamic stability and manage anticoagulation, their simultaneous application is rarely reported. We report a case of a deteriorating patient with secondary AML treated with simultaneous leukocytapheresis and CRRT. For the CRRT circuit, two separate hemodialysis catheters were placed in the femoral vein (access) and internal jugular vein (return). The leukocytapheresis circuit was then connected to the CRRT return line. The procedure was completed without immediate bleeding or thrombotic complications. Reductions in white blood cell counts, ammonia, and lactic acid levels were observed, along with improved oxygenation. Simultaneous leukocytapheresis and CRRT can be a safe and effective modality for the urgent management of hyperleukocytosis and TLS in critically ill patients.
2026-06-30 | T-cell replete haploidentical transplantation compared to mismatched unrelated allogeneic transplantation with post-transplantation cyclophosphamide in patients with secondary acute myeloid leukemia in first complete remission: A study from the ALWP/EBMT.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for secondary acute myeloid leukemia (sAML). Post-transplant cyclophosphamide has improved graft-versus-host disease (GVHD) prophylaxis, enabling the broader use of alternative donors. For patients lacking a human leukocyte antigen (HLA)-matched donor, haploidentical donor (Haplo) or 9/10 HLA mismatched unrelated donor (MMUD) HSCTs are widely used, yet their relative effectiveness in sAML is uncertain. We retrospectively compared outcomes after Haplo versus MMUD HSCT in adults with sAML in first complete remission transplanted between 2010 and 2022. Among 711 patients, 602 received Haplo and 109 MMUD grafts. Patient and transplant characteristics differed between cohorts, including donor age, conditioning intensity, graft source, and transplant year. Neutrophil recovery was faster after MMUD transplantation, while platelet recovery was comparable. Rates of acute and chronic GVHD, relapse incidence, non-relapse mortality, overall survival, leukemia-free survival, and GVHD-free/relapse-free survival were similar. Reduced intensity conditioning lowered acute GVHD risk, while peripheral blood grafts increased chronic GVHD. Lower Karnofsky score, older age and adverse-risk cytogenetics were adverse prognostic factors. Haplo and MMUD transplantation demonstrated comparable efficacy and safety with post-transplant cyclophosphamide, supporting both approaches as viable alternatives in the absence of an HLA-matched donor.
2026-06-25 | UCMSC-Exo for chemotherapy-induced myelosuppression in acute myeloid leukemia: a phase I clinical trial protocol.
Myelosuppression induced by chemotherapy represents a critical bottleneck for patients with hematological malignancies, leading to a series of severe complications responsible for chemotherapy dose reduction, interruptions, and even treatment-related death. There exists an urgent need for strategies to repair the bone marrow microenvironment and thus promote early recovery from myelosuppression. Umbilical cord-derived mesenchymal stem cell exosomes (UCMSC-Exo), as the key effector of stem cells, exhibit multi-target characteristics, making them a promising candidate for bone marrow structural reconstruction and functional remodeling. This study is a single-arm, open-label, dose-escalation, single-center, phase I clinical trial designed to evaluate the safety, tolerability, and preliminary efficacy of UCMSC-Exo in the treatment of chemotherapy-induced myelosuppression in patients with acute myeloid leukemia. Nine to eighteen eligible participants will be enrolled sequentially into three UCMSC-Exo dose-escalation groups to receive a single infusion, after which they will be followed up for 12 months. The primary endpoints focus on safety and tolerability. Secondary endpoints include parameters assessing myelosuppression recovery, the incidence of myelosuppression-related complications, and supportive care. The study protocol has been approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.Clinical trial registration: NCT06245746.
proteins
2026-08-12 | Treatment Modalities and the Impact of Granulocyte Colony-Stimulating Factor in AML Patients Treated With Venetoclax and Azacitidine: A DATAML Registry Study.
Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
2025-09-21 | Pathogenic mechanisms and targeted therapies for anemia in myelodysplastic syndromes.
Myelodysplastic Syndromes (MDS) are malignant neoplasms of the myeloid lineage originating from hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis, blood cell dysplasia, and a high risk of transformation to acute leukemia. Anemia affects up to 90 % of MDS patients, significantly increasing symptom burden, impacting quality of life, accelerating disease progression, and is associated with increased morbidity and mortality. The limited therapeutic landscape for addressing anemia in MDS presents a significant challenge in clinical management. This review explores the mechanisms of anemia in MDS（including low-risk MDS and high-risk MDS）, covering disturbances in hematopoiesis, telomere dynamics, inflammation, immune dysregulation, alterations in iron metabolism, and the role of the bone marrow microenvironment. We examine how these factors contribute to the complex pathophysiology of MDS-related anemia and discuss their implications for treatment strategies. Furthermore, we highlight recent advances in understanding the molecular basis of MDS, which have paved the way for novel therapeutic approaches. These include targeted therapies addressing specific genetic mutations, immunomodulatory agents, and innovative approaches to stimulate effective erythropoiesis. We also review emerging treatments such as Luspatercept, along with other novel agents targeting specific pathways, and ongoing clinical trials exploring combination therapies and personalized treatment strategies.
2025-05-28 | Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial.
6512 Background: In the phase 3 COMMANDS trial (NCT03682536), LUSPA was superior in improving red blood cell (RBC)-TI ≥12 wks with concurrent hemoglobin increase ≥1.5 g/dL in Wks 1 to 24 vs EA and had durable clinical benefit in pts with ESA-naive transfusion-dependent (TD) lower-risk MDS (LR-MDS; Della Porta MG, et al. Lancet Haematol . 2024; Garcia-Manero G, et al. ASH. 2024). Here, we report updated results including OS and duration of response. Methods: Eligible pts (≥18 yrs; ESA-naive; RBC TD; very low/low/intermediate-risk MDS) were randomized 1:1 (stratified by baseline [BL] RBC transfusion burden [TB], serum erythropoietin [EPO] level, and ring sideroblast [RS] status) to receive LUSPA (1.0-1.75 mg/kg) SC Q3W or EA (450-1050 IU/kg; max dose 80,000 IU) SC QW for ≥24 wks. Secondary endpoints included OS, duration of RBC-TI ≥12 wks, and safety. Results: As of Nov 4, 2024, median follow up (FU) was 29.0 and 27.1 mos for the LUSPA (n=182) and EA (n=181) groups, respectively. Median OS for LUSPA was not reached (NR) and was 46.7 mos for EA (HR, 0.86; 95% CI, 0.60-1.24); 3-yr OS rates were 63.8% and 62.2%, respectively, and 5-yr OS rates were 54.0% and 41.8%. In subgroups, similar OS trends were observed (Table). Overall, RBC-TI ≥12 wks (Wk 1 to end of treatment [EOT]) was reached by 76.4% (139/182) of pts in the LUSPA group and 55.8% (101/181) in the EA group. Median cumulative duration (95% CI) of RBC-TI ≥12 wks (sum of all durations of RBC-TI ≥12 wks episodes from Wk 1 to EOT) was 187.3 (119.6-NE) wks for LUSPA vs 94.9 (73.1-179.0) wks for EA (HR, 0.51; 95% CI, 0.34-0.77). Median duration (95% CI) of longest RBC-TI ≥12 wks period (from Wk 1 to EOT) was 126.6 (81.0-184.4) vs 86.7 (55.9-111.1) wks (HR, 0.64; 95% CI, 0.44-0.93). At cutoff, 24.7% of LUSPA pts and 11.2% of EA pts were on treatment; 84.6% and 82.7%, respectively, had ≥1 dose escalation. With longer FU, no new safety concerns emerged. Deaths occurred in both groups on- (10.4% vs 9.5%) and post-treatment (20.9% vs 26.3%). Progression to acute myeloid leukemia was comparable between groups (3.8% vs 4.4%). Conclusions: LUSPA led to improvements in response rate and duration, with a positive OS trend requiring further evaluation through more extended follow up. LUSPA signifies a new standard of care for anemia in first-line LR-MDS. Clinical trial information: NCT03682536 . Median OS, mos LUSPA EA HR (95% CI) Overall (ITT) (n=182)NR (n=181)46.7 0.86 (0.60-1.24) Stratification subgroup BL TB <4 U (n=118)NR (n=111)46.7 0.87(0.55-1.38) BL TB ≥4 U (n=64)NR (n=70)48.2 0.74(0.42-1.31) RS+ (n=133)NR (n=130)48.2 0.77(0.50-1.19) RS− (n=49)NR (n=50)46.2 0.93(0.50-1.75) BL EPO ≤200 U/L (n=145)NR (n=144)51.4 0.84(0.55-1.27) BL EPO >200 U/L (n=37)NR (n=37)35.4 0.81(0.40-1.64) ITT, intention-to-treat; U, units.
2024-07-12 | The Impact of Prophylactic Post-Chemotherapy G-CSF on the Relapse Rates in Patients with Acute Myeloid Leukemia: A Meta-Analysis.
This meta-analysis evaluated the impact of prophylactic post-chemotherapy granulocyte colony-stimulating factor (G-CSF) in patients with acute myeloid leukemia (AML). Overall, the relapse rate, overall survival, event-free survival, and mortality rate were similar in G-CSF (+) compared to G-CSF (-) patients. However, the relative risk (RR) of relapse was higher in children and in secondary AML patients who were treated with G-CSF compared to the G-CSF (-) group [RR, 95% confidence interval: 1.26, 1.04-1.52, and 1.12 (1.02-1.24)]. Treatment with post-chemotherapy G-CSF should be prescribed with caution in pediatric patients with AML and secondary AML as possibly increasing the relapse risk.
2024-02-27 | Treatment with the apoptosis inhibitor Asunercept reduces clone sizes in patients with lower risk Myelodysplastic Neoplasms
Abstract In low-risk Myelodysplastic Neoplasms (MDS), increased activity of apoptosis-promoting factors such as tumor necrosis factor (TNFα) and pro-apoptotic Fas ligand (CD95L) have been described as possible pathomechanisms leading to impaired erythropoiesis. Asunercept (APG101) is a novel therapeutic fusion protein blocking CD95, which has previously shown partial efficacy in reducing transfusion requirement in a clinical phase I trial for low-risk MDS patients (NCT01736436; 2012-11-26). In the current study we aimed to evaluate the effect of Asunercept therapy on the clonal bone marrow composition to identify potential biomarkers to predict response. Bone marrow samples of n = 12 low-risk MDS patients from the above referenced clinical trial were analyzed by serial deep whole exome sequencing in a total of n = 58 time points. We could distinguish a mean of 3.5 molecularly defined subclones per patient (range 2–6). We observed a molecular response defined as reductions of dominant clone sizes by a variant allele frequency (VAF) decrease of at least 10% (mean 20%, range: 10.5–39.2%) in dependency of Asunercept treatment in 9 of 12 (75%) patients. Most of this decline in clonal populations was observed after completion of 12 weeks treatment. Particularly early and pronounced reductions of clone sizes were found in subclones driven by mutations in genes involved in regulation of methylation ( n = 1 DNMT3A , n = 1 IDH2 , n = 1 TET2 ). Our results suggest that APG101 could be efficacious in reducing clone sizes of mutated hematopoietic cells in the bone marrow of Myelodysplastic Neoplasms, which warrants further investigation.
other
2026-08-24 | The roles of RUNX1 in megakaryocyte differentiation in myeloid leukemia.
Runt-related transcription factor 1/acute myeloid leukemia 1 (RUNX1/AML1) is essential for the generation of myeloid progenitor cells and differentiation of megakaryocytes (MKs). During megakaryocyte differentiation and maturation, RUNX1 forms transcriptional complexes with transcription factors such as GATA-1, Ets-1, Fli-1, and NF-E2 to promote platelet production. Disruption of RUNX1 is implicated in hematopoietic neoplasms like familial platelet disorder (FPD/AML), myelodysplastic syndrome (MDS) and acute myeloid leukemia. Here, we review the transcriptional regulation of RUNX1 in megakaryocyte differentiation of normal individuals and myeloid leukemia patients. We also summarize post-translational modifications (PTMs) of RUNX1 and discuss their potential implications for novel RUNX1-directed leukemia therapies.
2026-04-01 | mRNA vaccines in cancer immunotherapy: current progress and perspectives in solid tumors and hematologic malignancies.
The unprecedented success of mRNA vaccines during the COVID-19 pandemic has accelerated the development of nucleic acid-based therapeutics, particularly in oncology. Decades of foundational research on mRNA design, delivery, and immunogenicity have laid the groundwork for the application of mRNA vaccines in cancer treatment. Herein, we summarize the key principles of synthetic mRNA engineering, including the optimization of structural elements, nucleoside modification, and codon usage to improve stability, enhance translation efficiency, and modulate immune responses. We highlight diverse antigen strategies, including tumor-associated antigens; neoantigens; and novel sources, such as cryptic antigens, aberrant splicing variants, and transposable element-derived antigens. We discuss delivery platforms, particularly lipid nanoparticles (LNPs) and dendritic cell-based systems, in the context of improving mRNA biodistribution and immune activation. We further examine how mRNA vaccines stimulate antitumor responses by encoding antigens, modulating the tumor microenvironment, and supporting adoptive T cell therapies. We review preclinical and clinical advances in combining mRNA vaccine with immune checkpoint inhibitors for the treatment of solid tumors (e.g., melanoma, pancreatic cancer, and glioblastoma) and hematologic malignancies (e.g., acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma). Finally, we explore emerging innovations, such as targeted LNP platforms for in vivo chimeric antigen receptor T/T cell receptor T engineering and artificial intelligence-assisted vaccine design, underscoring the transformative potential of mRNA technology in cancer immunotherapy.
2025-10-18 | Acute Leukemias of Ambiguous Lineage With RUNX1 Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With RUNX1 Mutations: A Study From the Bone Marrow Pathology Group.
The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS-related AML (AML-MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi-institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS-related cytogenetics, BCR::ABL1, KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL-RUNX1 and AML-RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS-associated genes. No ALAL-RUNX1 or AML-RUNX1 cases showed concomitant TP53 mutation. ALAL-RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML-directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL-RUNX1; however, it did not reach significance. Our results suggest ALAL-RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML-RUNX1. Our findings suggest, like other MR mutations, RUNX1-mutated ALALs should be included within AML-MR.
2025-04-21 | Abstract 6500: Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms
Abstract Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with cytogenetic abnormalities of chromosome 7 have dismal survival outcomes. Monosomy 7 or deletion of 7q (-7/del7q) are adverse-risk cytogenetic features found in up to 12% of MDS/AML patients and are further enriched in therapy-related MDS/AML. Despite significant scientific effort, no targeted therapy is available for patients with -7/del7q MDS/AML. Several genes are associated with -7/del7q leukemogenesis. Cut-like homeobox 1 (CUX1) is a gene encoding a context-dependent transcription factor required for several molecular pathways, including epigenetic signaling. CUX1 is deleted in -7/del7q MDS/AML and somatically mutated in 2-4% of MDS/AML. CUX1 mutations and CUX1 deletions are associated with a poor prognosis, and are known to co-occur with adverse risk TP53 mutations and a complex cytogenetic background. Thus, there is a need for novel human models of MDS/AML to isolate the effect of CUX1 alterations. To address the need for high-fidelity models of MDS/AML with high-risk genetic changes, we transfected human inducible pluripotent stem cells (hiPSCs) with CUX1 targeting gRNA and CRISPR/Cas9 ribonucleotide-protein (RNP) complexes to generate isogenic hiPSC lines bearing CUX1+/- and CUX1-/- genotypes alongside parent hiPSCs and sham transfection lines with a CUX1+/+ background. These derivative cell lines underwent rigorous validation by karyotypic G-banding analysis, sequencing, immunoblotting, trilineage germ layer differentiation, and analysis of hiPSC transcriptional and immunophenotypic markers. We hypothesized that the loss of one or both alleles of CUX1 would result in transcriptional changes similar to CUX1 mutated and -7/del7q MDS/AML. This model can be further leveraged to identify potential treatment targets. We obtained bulk RNA sequencing of undifferentiated hiPSCs and hiPSC-derived hematopoietic stem and progenitor cells (i-HSPCs) of each genotype (CUX1+/+, CUX1+/-, and CUX1-/-). We identified several differentially expressed genes and novel long non-coding RNAs in hiPSCs with Cas9-mediated CUX1 deletions, including downregulation of distinct subsets of genes in CUX1-/- and CUX1+/- hiPSCs. Bulk RNA sequencing of CUX1-/- and CUX1+/- i-HSPCs identified an association between reduced expression of thioredoxin-interacting protein (TXNIP), a known regulator of autophagy. This study supports the use of hiPSC-based CRISPR/Cas9 gene editing as a novel platform to identify gene-specific alterations in genotypically and cytogenetically complex myeloid neoplasms. Citation Format: Joseph Michael Cannova, Kaina A. Millan, Yuqing Xue, Aubrianna S. Ramsland, Zara Khosravi, Adesewa Ogunsusi, Matthew Jotte, Megan McNerney, Michael Drazer. Application of human inducible pluripotent stem cells (hiPSCs) with CRISPR/Cas9-mediated deletion of CUX1 as a model for high-risk myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6500.
2024-10-29 | AML-VAC-XS15-01: protocol of a first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of a multi-peptide vaccine based on leukemia stem cell antigens in acute myeloid leukemia patients.
Acute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome. Based on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial's primary objectives are the assessment of the vaccine's immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy. The AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.
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